ETAA1 ensures proper chromosome segregation: A matter of S phase or mitosis?

Abstract

ETAA1 activates the master checkpoint kinase ATR. Bass and Cortez (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201810058) recently reported an intra-mitotic function of ETAA1 that safeguards chromosome stability. In this issue, Achuthankutty et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201905064) describe a mechanism controlling the ATR-activating potential of ETAA1 in S phase to preserve chromosome stability.

Figure 1.

ETAA1 safeguards chromosome stability independently of TopBP1. Upon replication stress during S phase, TopBP1-dependent activation of ATR drives Chk1-dependent cell cycle arrest and DNA repair. In addition, S phase–specific stimulatory phosphorylation of ETAA1 at its AAD activates ATR to avoid premature mitotic entry, CIN, and cell death. It is still unclear whether this function of ETAA1 requires Chk1 and whether ETAA1 phosphorylation (yellow circles) regulates the ETAA1-ATR-Chk1-FOXM1 axis, which prevents an untimely transition to G2. During mitosis, ETAA1 activates ATR, possibly at centromeric R-loops, leading to Chk1 and Aurora B activation to prevent chromosome misalignment. The contribution to cell survival of this intra-mitotic role of ETAA1 remains undefined.